Bottom Line:
New, adult-generated dentate gyrus progenitors, in which the PC3 transgene was expressed, showed accelerated differentiation and significantly reduced dendritic arborization and spine density.Functionally, this genetic manipulation specifically affected different hippocampus-dependent learning and memory tasks, including contextual fear conditioning, and selectively reduced synaptic plasticity in the dentate gyrus.Thus, the correct unwinding of these key memory functions, which can be an expression of the ability of adult-generated neurons to link subsequent events in memory circuits, is critically dependent on the correct timing of the initial stages of neuron maturation and connection to existing circuits.

ABSTRACTAdult neurogenesis in the dentate gyrus plays a critical role in hippocampus-dependent spatial learning. It remains unknown, however, how new neurons become functionally integrated into spatial circuits and contribute to hippocampus-mediated forms of learning and memory. To investigate these issues, we used a mouse model in which the differentiation of adult-generated dentate gyrus neurons can be anticipated by conditionally expressing the pro-differentiative gene PC3 (Tis21/BTG2) in nestin-positive progenitor cells. In contrast to previous studies that affected the number of newly generated neurons, this strategy selectively changes their timing of differentiation. New, adult-generated dentate gyrus progenitors, in which the PC3 transgene was expressed, showed accelerated differentiation and significantly reduced dendritic arborization and spine density. Functionally, this genetic manipulation specifically affected different hippocampus-dependent learning and memory tasks, including contextual fear conditioning, and selectively reduced synaptic plasticity in the dentate gyrus. Morphological and functional analyses of hippocampal neurons at different stages of differentiation, following transgene activation within defined time-windows, revealed that the new, adult-generated neurons up to 3-4 weeks of age are required not only to acquire new spatial information but also to use previously consolidated memories. Thus, the correct unwinding of these key memory functions, which can be an expression of the ability of adult-generated neurons to link subsequent events in memory circuits, is critically dependent on the correct timing of the initial stages of neuron maturation and connection to existing circuits.

pbio-0060246-g005: Effect of Premature Differentiation of Adult-Generated Granule Cells on Hippocampal Synaptic Plasticity(A) LTP of lateral perforant pathway synapses in the dentate gyrus is reduced in TgPC3 ON but not in TgPC3 OFF mice. Upper panel shows traces of fEPSPs immediately before (black traces) and after 50 min (gray traces) of high-frequency trains in WT, TgPC3 ON, and OFF mice. Averages of 10 traces for each example are shown. The stimulus artifact was digitally removed for display purposes. Scales: 5 ms and 100 μV wt; 25 μV TgPC3 OFF; 60 μV TgPC3 ON.(B) LTP of Schaffer collateral synapses measured in CA1 was unaffected by early PC3 gene activation (p > 0.2). Upper panel: representative fEPSPs before (black traces) and after (gray traces) high frequency stimulations in all conditions. Shown are averages of 10 traces each. The stimulus artifact was digitally removed for display purposes. Scales: 5 ms and 60 μV wt; 100 μV TgPC3 OFF; 100 μV TgPC3 ON.(C) The slope of input-output (I/O) curves at perforant-path synapses in dentate gyrus was similar in all three conditions.

Mentions:
Long-term changes in synaptic strength have been described in several brain areas. In particular, hippocampal long-term potentiation (LTP) of glutamatergic synaptic transmission is believed to be the synaptic correlate of several forms of learning and memory (for reviews, see [61,62]). To test whether the above-described deficits in memory tasks caused by early expression of the PC3 gene correlated with a change in long-term synaptic transmission, we recorded field excitatory postsynaptic potentials (fEPSPs) in the outer molecular layer of the dentate gyrus while stimulating perforant path afferents in WT, TgPC3 OFF, and TgPC3 ON mice. Robust LTP of excitatory synaptic transmission could be evoked by high-frequency stimulations (HFS: four trains of 100 stimuli at 100 Hz) in WT animals. Overall, fEPSP slopes were 1.5 ± 0.04 larger when measured 50 min after LTP induction and compared with baseline levels (n = 13 slices, 7 mice; p < 0.001; Figure 5A). Similar levels of synaptic potentiation were observed in TgPC3 OFF animals (normalized fEPSP slope at 50 min after HFS = 1.62 ± 0.12, n = 9 slices, 7 mice, p > 0.2 when compared with WT, Figure 5A). In TgPC3 ON mice, HFS evoked LTP consistently (normalized fEPSP slope was 1.2 ± 0.04, n = 12 slices, 7 mice, p < 0.001), but we found that the level of potentiation was significantly smaller when compared to WT and TgPC3 OFF mice (p < 0.001; Figure 5A). This effect on LTP was not due to overall changes in synaptic transmission, as input-output curves (fEPSP slopes versus increasing afferent fiber volley amplitudes) were similar in WT, TgPC3 OFF, and TgPC3 ON mice (Figure 5C).

Bottom Line:
New, adult-generated dentate gyrus progenitors, in which the PC3 transgene was expressed, showed accelerated differentiation and significantly reduced dendritic arborization and spine density.Functionally, this genetic manipulation specifically affected different hippocampus-dependent learning and memory tasks, including contextual fear conditioning, and selectively reduced synaptic plasticity in the dentate gyrus.Thus, the correct unwinding of these key memory functions, which can be an expression of the ability of adult-generated neurons to link subsequent events in memory circuits, is critically dependent on the correct timing of the initial stages of neuron maturation and connection to existing circuits.

ABSTRACTAdult neurogenesis in the dentate gyrus plays a critical role in hippocampus-dependent spatial learning. It remains unknown, however, how new neurons become functionally integrated into spatial circuits and contribute to hippocampus-mediated forms of learning and memory. To investigate these issues, we used a mouse model in which the differentiation of adult-generated dentate gyrus neurons can be anticipated by conditionally expressing the pro-differentiative gene PC3 (Tis21/BTG2) in nestin-positive progenitor cells. In contrast to previous studies that affected the number of newly generated neurons, this strategy selectively changes their timing of differentiation. New, adult-generated dentate gyrus progenitors, in which the PC3 transgene was expressed, showed accelerated differentiation and significantly reduced dendritic arborization and spine density. Functionally, this genetic manipulation specifically affected different hippocampus-dependent learning and memory tasks, including contextual fear conditioning, and selectively reduced synaptic plasticity in the dentate gyrus. Morphological and functional analyses of hippocampal neurons at different stages of differentiation, following transgene activation within defined time-windows, revealed that the new, adult-generated neurons up to 3-4 weeks of age are required not only to acquire new spatial information but also to use previously consolidated memories. Thus, the correct unwinding of these key memory functions, which can be an expression of the ability of adult-generated neurons to link subsequent events in memory circuits, is critically dependent on the correct timing of the initial stages of neuron maturation and connection to existing circuits.